Project Summary/Abstract Title: Dissecting the Role of Src Family Kinases in Breast Cancer Brain Metastasis PI: Siyuan Zhang, M.D., Ph.D., The University of Texas M.D. Anderson Cancer Center I received my M.D. in 1998 from Peking University Health Science Center and a Ph.D. degree in Cancer Biology from the National University of Singapore in 2005. My Ph.D. training was focused on deciphering the molecular mechanisms of the anti-cancer activity of parthenolide - an active component in natural product feverfew. I was the first author in 7 of the 9 papers I published during Ph.D. training. I joined Dr. Dihua Yu's group at The University of Texas M.D. Anderson Cancer (MDACC) in 2007 to pursue my goal of making discoveries of clinical impact. My research elucidated a key mechanism of trastuzumab resistance and led to the development of a novel clinically-translatable combinatorial regimen for trastuzumab-resistant patients. Meanwhile, I am also investigating the role of PTEN loss in breast cancer brain metastasis. My current research goal is to study the role of certain genetic alterations in breast cancer brain metastasis and establish myself as an independent researcher through K99 funding. My long-term research goal will be focused on two important areas: (1) Basic research, investigate the mechanisms of metastasis by focusing on the contribution of the pre-metastatic microenvironment; and (2) Translational research, based on basic research findings to identify, design and pre-clinically test novel therapeutic regimens for treatment of cancer metastasis. To achieve my short-term and long-term career goals, during the K99 mentored phase of this grant, I will receive comprehensive training based in an unmatched training environment for cancer research- MDACC. I will cooperate with my mentors and actively participate in formal courses, workshops and seminars to broaden my knowledge and skills, particularly in genetically-engineered mouse models. The career development training in scientific writing, research ethics, lab management and leadership skills will further facilitate my transition as an independent scientist. My research plan is focused on the role of Src family kinases (SFK) in breast cancer brain metastasis. Among 1.3 million women diagnosed with breast cancer every year worldwide, about 10- 16% will develop brain metastases. Even with most advanced clinical care, the overall survival for brain metastasis patients is less than 14 months from diagnosis. At present, no effective treatment exists for patients with refractory metastatic breast cancer brain metastasis. Therefore, novel and effective therapeutic approaches are urgently needed for this population. Unfortunately, developing effective therapeutics for brain metastasis is largely hampered by a shortage of in-depth understanding of the basic mechanisms of brain metastasis. Our preliminary studies suggest that Src family kinase c-Src plays an important role in both metastatic tumor cells and brain metastasis microenvironments. The major goal of the proposed project is to use innovative approaches to dissect the role of Src family kinases in the brain metastasis process and develop novel therapies for breast cancer brain metastasis patients. We propose three comprehensive aims: 1) Aim 1 (K99 phase): Determine the role of tumor SFK activation in breast cancer brain metastasis. 2) Aim 2 (R00 Phase): Determine the impact of SFK activation in the brain pre-metastatic microenvironment on breast cancer brain metastasis. 3) Aim 3 (R00 Phase): Investigate the pre-clinical efficacy of novel SFK-targeting therapeutic regimens in the treatment of breast cancer brain metastasis. Success of the project will promote my career transition from my position as a mentored postdoctoral fellow to becoming an independent scientist with my own research direction. More importantly, novel insights from this study into the mechanisms of breast cancer brain metastasis will guide the development of novel clinically-translatable regimens that offer fresh opportunities for the treatment of a devastatingly intractable disease.